Alzheimer disease (AD) is a heterogeneous and complex disorder and both genetic and environmental factors are likely to be involved in its etiology. Hundreds of putative susceptibility genes for late-onset AD have been reported, but the majority of these claims?with the exception of the e4 allele of the apolipoprotein E gene? have not been consistently replicated. Furthermore, the functional significance of the majority of the positional candidate genes in AD pathogenesis is not clear. One putative environmental (viral) factor that has been implicated is human cytomegalovirus (CMV). Recent studies have established that CMV infection is associated with an increased risk of AD, and that several immunological and virological features of CMV infection correlate with clinical and pathological measures of this disease. It is clear, however, that not all equally exposed people are equally likely to develop CMV-spurred AD, suggesting the involvement of host genetic factors that could modify immunity to this virus. CMV has evolved a large repertoire of immunoevasion strategies. One strategy involves generating proteins that have functional properties of the Fc? receptor (Fc?R), which may enable the virus to evade host immunosurveillance by evading the effector consequences of anti-CMV antibody binding, such as antibody-dependent cellular cytotoxicity. We have shown that alleles of a major gene complex of the immune system?GM (? marker) allotypes?modulate this viral strategy. We have also shown that particular GM genotypes contribute to the magnitude of antibody responsiveness to CMV glycoprotein B (gB), which is conserved in herpesviruses because of its important role in infectivity, viral attachment and entry. Based on these observations, we hypothesize that GM genes are effect modifiers of CMV-AD association, and the underlying mechanisms include their contribution to anti-CMV immunity and their modulating influence on the viral immunoevasion strategies. The following specific aims will test our hypothesis: 1) Determine if GM alleles modulate the AD risk associated with CMV infection: DNA from 3 large longitudinal aging cohorts?most of which have been characterized for anti-CMV antibodies?will be genotyped for several GM alleles. We will determine whether GM alleles are risk factors for AD, influence anti-CMV antibody responsiveness, and thus act as effect modifiers of CMV-AD association; 2) Determine if CMV-encoded Fc?R proteins bind differentially to genetically disparate Fc? (GM) regions of anti-CMV IgG antibodies in AD patients: DNA encoding the ectodomains of TRL11/IRL11, RL-13, and UL119-UL118 Fc?Rs will be cloned and expressed in mammalian cells by standard methods. Using IgG subclass-specific affinity chromatography and sera from AD patients, we will purify IgG antibodies directed against CMV gB. Comparative affinities of allotypically disparate IgG molecules to the CMV Fc?Rs will be monitored by surface plasmon resonance. This proposal opens a new avenue of investigation towards our understanding of the host immunogenetic factors involved in the etiopathogenesis of AD. Results from this investigation could lead to novel immunotherapies against AD.